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Kanematsu-Yamaki, Yoko; Nishizawa, Naoki; Kaisho, Tomoko; Nagai, Hiroaki; Mochida, Taisuke; Asakawa, Tomoko; Inooka, Hiroshi; Dote, Katsuko; Fujita, Hisashi; Matsumiya, Kouta; Hirabayashi, Hideki; Sakamoto, Junichi; Ohtaki, Tetsuya; Takekawa, Shiro; Asami, Taiji
Journal of medicinal chemistry, 07/2017, Letnik: 60, Številka: 14Journal Article
Neuromedin U (NMU) is a neuropeptide that mediates a variety of physiological functions via its receptors, NMUR1 and NMUR2. Recently, there has been an increased focus on NMU as a promising treatment option for diabetes and obesity. A short form of NMU (NMU-8) has potent agonist activity for both receptors but is metabolically unstable. Therefore, we designed and synthesized NMU-8 analogues modified by polyethylene glycol (PEG; molecular weight, 20 kDa; PEG20k) via a linker. 3-(2-Naphthyl)alanine substitution at position 19 increased NMUR2 selectivity of NMU-8 analogues with retention of high agonist activity. Compound 37, an NMUR2-selective PEG20k analogue containing piperazin-1-ylacetyl linker, exhibited a potent body weight-lowering effect with concomitant inhibition of food intake in a dose-dependent manner (body weight loss of 12.4% at 30 nmol/kg) by once-daily repeated dosing for 2 weeks in mice with diet-induced obesity.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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